Sandra N. Moses

Retrograde amnesia after hippocampal damage: Recent vs. remote memories in two tasks

We review evidence from experiments conducted in our laboratory on retrograde amnesia in rats with damage to the hippocampal formation. In a new experiment reported here, we show that N‐methyl‐D‐aspartate (NMDA)‐induced hippocampal damage produced retrograde amnesia for both hidden platform and two‐choice visible platform discriminations in the Morris water task. For both problems there was a significant trend for longer training‐surgery intervals to be associated with worse retention performance. Little support is offered by our work for the concept that there is a process involving hippocampal‐dependent consolidation of memories in extrahippocampal permanent storage sites. Long‐term memory consolidation may take place within the hippocampus. The hippocampus may be involved permanently in storage and/or retrieval of a variety of relational and nonrelational memories if it was intact at the time of learning, even involving information which is definitely not affected in anterograde amnesia after hippocampal damage. Hippocampus 2001;11:27–42.

Detection and Localization of Hippocampal Activity Using Beamformers with MEG: A Detailed Investigation Using Simulations and Empirical Data

The ability to detect neuronal activity emanating from deep brain structures such as the hippocampus using magnetoencephalography has been debated in the literature. While a significant number of recent publications reported activations from deep brain structures, others reported their inability to detect such activity even when other detection modalities confirmed its presence. In this article, we relied on realistic simulations to show that both sides of this debate are correct and that these findings are reconcilable. We show that the ability to detect such activations in evoked responses depends on the signal strength, the amount of brain noise background, the experimental design parameters, and the methodology used to detect them. Furthermore, we show that small signal strengths require contrasts with control conditions to be detected, particularly in the presence of strong brain noise backgrounds. We focus on one localization technique, the adaptive spatial filter (beamformer), and examine its strengths and weaknesses in reconstructing hippocampal activations, in the presence of other strong brain sources such as visual activations, and compare the performance of the vector and scalar beamformers under such conditions. We show that although a weight‐normalized beamformer combined with a multisphere head model is not biased in the presence of uncorrelated random noise, it can be significantly biased in the presence of correlated brain noise. Furthermore, we show that the vector beamformer performs significantly better than the scalar under such conditions. We corroborate our findings empirically using real data and demonstrate our ability to detect and localize such sources. Hum Brain Mapp, 2011.

M50 sensory gating predicts negative symptoms in schizophrenia.

Impaired auditory sensory gating is considered characteristic of schizophrenia and a marker of the information processing deficit inherent to that disorder. Predominance of negative symptoms also reflects the degree of deficit in schizophrenia and is associated with poorer pre-morbid functioning, lower IQ, and poorer outcomes. However, a consistent relationship between auditory sensory gating and negative symptoms in schizophrenia has yet to be demonstrated. The absence of such a finding is surprising, since both impaired auditory gating and negative symptoms have been linked with impaired fronto-temporal cortical function. The present study measured auditory gating using the P50 event related potential (ERP) in a paired-click paradigm and capitalized on the relative localization advantage of magnetoencephalography (MEG) to assess auditory sensory gating in terms of the event related field (ERF) M50 source dipoles on bilateral superior temporal gyrus (STG). The primary hypothesis was that there would be a positive correlation between lateralized M50 auditory sensory gating measures and negative symptoms in patients with schizophrenia. A standard paired-click paradigm was used during simultaneous EEG and MEG data collection to determine S2/S1 sensory gating ratios in a group of 20 patients for both neuroimaging techniques. Participants were administered the Schedule for the Assessment of Negative Symptoms (SANS), the Positive and Negative Symptom Scale (PANSS), and the Calgary Depression Scale for Schizophrenia. Consistent with previous reports, there was no relationship between ERP P50 sensory gating and negative symptoms. However, right (not left) hemisphere ERF M50 sensory gating ratio was significantly and positively correlated with negative symptoms. This finding is compatible with information processing theories of negative symptoms and with more recent findings of fronto-temporal abnormality in patients with predominantly negative symptoms.

Predicting EEG responses using MEG sources in superior temporal gyrus reveals source asynchrony in patients with schizophrenia

OBJECTIVE An integrated analysis using Electroencephalography (EEG) and magnetoencephalography (MEG) is introduced to study abnormalities in early cortical responses to auditory stimuli in schizophrenia. METHODS Auditory responses were recorded simultaneously using EEG and MEG from 20 patients with schizophrenia and 19 control subjects. Bilateral superior temporal gyrus (STG) sources and their time courses were obtained using MEG for the 30-100 ms post-stimulus interval. The MEG STG source time courses were used to predict the EEG signal at electrode Cz. RESULTS In control subjects, the STG sources predicted the EEG Cz recording very well (97% variance explained). In schizophrenia patients, the STG sources accounted for substantially (86%) and significantly (P<0.0002) less variance. After MEG-derived STG activity was removed from the EEG Cz signal, the residual signal was dominated by 40 Hz activity, an indication that the remaining variance in EEG is probably contributed by other brain generators, rather than by random noise. CONCLUSIONS Integrated MEG and EEG analysis can differentiate patients and controls, and suggests a basis for a well established abnormality in the cortical auditory response in schizophrenia, implicating a disorder of functional connectivity in the relationship between STG sources and other brain generators.

Differential contributions of hippocampus, amygdala and perirhinal cortex to recognition of novel objects, contextual stimuli and stimulus relationships.

This study examined contributions of the hippocampus, amygdala and perirhinal cortex to memory. Rats performed a cover task, and changes to stimulus identity or relationships were used to test incidental memory. Rats with hippocampal damage showed deficient responses to relationship changes, but demonstrated knowledge of the position and identity of the target object. They over-focused on the most predictive stimuli, and failed to acquire associations including surrounding cues. Rats with amygdala damage responded to changes involving distal stimuli, and showed deficient responses to novel objects and object relationships. These rats may be highly reliant on relational representations, resulting in a reduced salience for individual novel stimuli. Rats with perirhinal damaged responded to novel stimulus relationships and distal cues, but showed deficient responses to novel objects, suggesting that changes in identity had reduced salience. Implications for declarative and conjunctive hippocampal theories are discussed.

An investigation of learning strategy supporting transitive inference performance in humans compared to other species

Generalizations about neural function are often drawn from non-human animal models to human cognition, however, the assumption of cross-species conservation may sometimes be invalid. Humans may use different strategies mediated by alternative structures, or similar structures may operate differently within the context of the human brain. The transitive inference problem, considered a hallmark of logical reasoning, can be solved by non-human species via associative learning rather than logic. We tested whether humans use similar strategies to other species for transitive inference. Results are crucial for evaluating the validity of widely accepted assumptions of similar neural substrates underlying performance in humans and other animals. Here we show that successful transitive inference in humans is unrelated to use of associative learning strategies and is associated with ability to report the hierarchical relationship among stimuli. Our work stipulates that cross-species generalizations must be interpreted cautiously, since performance on the same task may be mediated by different strategies and/or neural systems.

Dynamic neural activity recorded from human amygdala during fear conditioning using magnetoencephalography

Magnetoencephalography (MEG) was used to record the dynamics of amygdala neuronal population activity during fear conditioning in human participants. Activation during conditioning training was compared to habituation and extinction sessions. Conditioned stimuli (CS) were visually presented geometric figures, and unconditioned stimuli (US) were aversive white-noise bursts. The CS+ was paired with the US on 50% of presentations and the CS- was never paired. The precise temporal resolution of MEG allowed us to address the issue of whether the amygdala responds to the onset or offset of the CS+, and/or the expectation of the initiation or offset of the an omitted auditory US. Fear conditioning elicited differential amygdala activation for the unpaired CS+ compared to the CS-, extinction and habituation. This was especially robust in the right hemisphere at CS onset. The strongest peaks of amygdala activity occurred at an average of 270 ms in the right and 306 ms in the left hemisphere following unpaired CS+ onset, and following offset at 21 ms in the left and 161 ms in the right (corresponding to an interval of 108 ms and 248 ms after the anticipated onset of the US, respectively). However, the earliest peaks in this epoch preceded US onset in most subjects. Thus, the activity dynamics suggest that the amygdala both differentially responds to stimuli and anticipates the arrival of stimuli based on prior learning of contingencies. The amygdala also shows stimulus omission-related activation that could potentially provide feedback about experienced stimulus contingencies to modify future responding during learning and extinction.

MEG reveals different contributions of somatomotor cortex and cerebellum to simple reaction time after temporally structured cues

Magnetoencephalography (MEG) was used to measure brain activity while participants performed a simple reaction to targets after either a random interval (uncued targets) or a series of isochronous warning stimuli with 200‐ms intervals that acted as a countdown. Targets could arrive “on time” or “early” relative to the preceding warning stimuli. Cerebellar activity before any stimulus onset predicted uncued simple reaction time. Onset of activity in somatomotor cortex relative to the target predicted reaction time after two warning stimuli when the target arrived on time or early. After three warning stimuli, when the target arrived on time and was certain to occur, prestimulus cerebellar activity and somatomotor onset were significant predictors of reaction time. When the target arrived early after three warning stimuli, prestimulus cerebellar and cingulate activity were predictive. The cerebellar results may reflect a number of possible factors, including a role in timing, response readiness, prediction and attention. Hum. Brain Mapping 2005.

Hippocampus volume and episodic memory in schizophrenia.

Previous studies of schizophrenia have suggested a linkage between neuropsychological (NP) deficits and hippocampus abnormality. The relationship between hippocampus volume and NP functioning was investigated in 24 patients with chronic schizophrenia and 24 matched healthy controls. Overall intracranial, white and gray matter, and anterior (AH) and posterior (PH) hippocampus volumes were assessed from magnetic resonance images (MRI). NP domains of IQ, attention, and executive function were also evaluated with respect to volumetric measures. It was hypothesized that AH and PH volumes and episodic memory scores would be positively associated in controls and that the schizophrenia group would depart from this normative pattern. NP functioning was impaired overall and AH volume was smaller in the schizophrenia group. In the controls, the hippocampus-memory relationships involved AH and PH, and correlations were significant for verbal memory measures. In the schizophrenia group, positive correlations were constrained to PH. Negative correlations emerged between AH and verbal and visual memory measures. For both groups, cortical volume negatively correlated with age, but a negative correlation between age and hippocampus volume was found only in the schizophrenia group. In this sample of adults with schizophrenia, atypical relationships between regional hippocampus volumes and episodic memory ability were found, as was an atypical negative association between hippocampus volume and age.

Impaired secondary somatosensory gating in patients with schizophrenia

A large and growing literature has demonstrated a deficit in auditory gating in patients with schizophrenia. Although that deficit has been interpreted as a general gating problem, no deficit has been shown in other sensory modalities. Recent research in our laboratory has examined sensory gating effects in the somatosensory system showing no difference in gating of the primary somatosensory response between patients with schizophrenia and control subjects. This is consistent with recent structural studies showing no cortical structural abnormality in primary somatosensory area in schizophrenia. However, a significant decrease in cortical thickness and gray matter volume loss in secondary somatosensory cortex has recently been reported, suggesting this as a focus for impaired somatosensory gating. Thus, the current study was designed (1) to replicate previous work showing a lack of schizophrenia deficit in primary somatosensory cortex (SI) gating, and (2) to investigate a possible deficit in secondary somatosensory cortex (SII) gating. In a paired-pulse paradigm, dipolar sources were assessed in SI and SII contralateral to unilateral median nerve stimulation. Patients demonstrated no impairment in SI gating, but a robust gating deficit in SII, supporting the presence of cross modal gating deficits in schizophrenia.